Flightless I deficiency enhances wound repair by increasing cell migration and proliferation

Abstract

Wound healing disorders are a therapeutic problem of increasing clinical importance involving substantial morbidity, mortality, and rising health costs. Our studies investigating flightless I (FliI), a highly conserved actin-remodelling protein, now reveal that FliI is an important regulator of wound repair whose manipulation may lead to enhanced wound outcomes. We demonstrate that FliI-deficient + /- mice are characterized by improved wound healing with increased epithelial migration and enhanced wound contraction. In contrast, FliI-overexpressing mice have significantly impaired wound healing with larger less contracted wounds and reduced cellular proliferation. We show that FliI is secreted in response to wounding and that topical application of antibodies raised against the leucine-rich repeat domain of the FliI protein (FliL) significantly improves wound repair. These studies reveal that FliI affects wound repair via mechanisms involving cell migration and proliferation and that FliI might represent an effective novel therapeutic factor to improve conditions in which wound healing is impaired.

Attenuation of flightless I improves wound healing and enhances angiogenesis in a murine model of type 1 diabetes

“…Diabetic wounds treated with FnAb showed accelerated wound closure with a 1.9-fold decrease in average wound size observed in day 3 and day 7 WT FnAb-treated diabetic wounds. Similar effects have been reported in previous studies where FnAb improved the rate of incisional [17], excisional [20] and burn wound repair [19]. Dose-dependent effects of FnAb on cellular proliferation have also previously been demonstrated [20] and the addition of FnAb to human chronic wound fluids can reduce their inhibitory effect on cell proliferation in vitro [18].…”

“…Human diabetic wounds have elevated levels of FLII, a cytoskeletal protein previously shown to inhibit cellular migration, adhesion and proliferation and to negatively impact on the wound repair process [17]. To determine the extent of the involvement of FLII in diabetic wound healing, mice with low Flii +/− , normal (WT) and high (Flii Tg/Tg ) expression of Flii gene were rendered diabetic and assessed for their healing characteristics.…”

“…FLII is secreted by both fibroblasts and macrophages [10,17] and is present in acute and chronic human wound fluid [18]. FLII is secreted through a non-classic late endosome/ lysosome-mediated pathway by at least two of the major cell types found in wounds, fibroblasts and macrophages [10], and is able to bind to lipopolysaccharide and alter macrophage activation [10].…”

Flightless, secreted through a late endosome/lysosome pathway, binds LPS and dampens cytokine secretion

“…The actions of Flii described to date involve intracellular Flii, however, results suggest that Flii may also be secreted (Cowin et al, 2007). We now show that Flii is secreted through a nonclassical late endosome/lysosome-mediated pathway by at least two of the major cell types found in wounds: fibroblasts and macrophages.…”

“…Like other members of this family it binds actin and has F-actin severing activity via these domains (Goshima et al, 1999;Liu and Yin, 1998). As may be expected for an actin-remodelling protein, Flii regulates fibroblast and keratinocyte migration both in vitro and in vivo (Cowin et al, 2007). Many actin-binding proteins, including gelsolin family members, also have a role within the nucleus and Flii is no exception (Lee et al, 2004;Lee and Stallcup, 2006;Liu and Yin, 1998).…”